From Klinefelter Syndrome to High Grade Aneuploidies: Expanding the Gene-dosage Effect of Supernumerary X Chromosomes

Matteo Spaziani, Francesco Carlomagno, Chiara Tarantino, Francesco Angelini, Roberto Paparella, Luigi Tarani, Carolina Putotto, Roberto Badagliacca, Carlotta Pozza, Andrea M Isidori, Daniele Gianfrilli
The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 8, August 2024, Pages e1564–e1573
https://doi.org/10.1210/clinem/dgad730

Abstract

Objective

High-grade aneuploidies of X and Y sex chromosomes (HGAs) are exceedingly rare and complex conditions. We aimed to investigate the effect of supernumerary X chromosomes (extra-Xs) on the clinical, hormonal, metabolic, and echocardiographic features of patients with HGAs.

Design and Methods

In a cross-sectional study, we compared 23 subjects with HGAs and 46 age-matched subjects with 47,XXY Klinefelter syndrome (KS), according to the number of extra-Xs: two (47,XXY and 48,XXYY), three (48,XXXY and 49,XXXYY), or four supernumerary Xs (49,XXXXY). A second cohort consisting of 46 pubertal stage-matched KS subjects was employed for validation. Clinical, hormonal, metabolic and ultrasonographic parameters were collected and analyzed.

Results

The increase in the number of extra-Xs was associated with a progressive adverse effect on height, pubertal development, testicular volume and function, adrenal steroidogenesis, and thyroid function. A progressive linear increase in ACTH and a decrease in cortisol/ACTH ratios were found. Weight and body mass index, Sertoli cell function, lipid profile, and glucose tolerance post-oral glucose tolerance test were all worse in the HGA cohort compared to KS. Cardiac evaluation revealed a linear association with reduced left and right end-diastolic diameters and reduced ejection fraction.

Conclusion

The increase in the number of extra-Xs is associated with a “dose-dependent” progressive impairment in steroid producing glands, thyroid function, cardiac structure, and performance.

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